Metal alkoxide taxane and β-lactam compounds

ABSTRACT

A process for preparing N-acyl, N-sulfonyl and N-phosphoryl substituted isoserine esters in which a metal alkoxide is reacted with a β-lactam.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation application based on U.S. Ser. No.08/941,640, filed Sep. 30, 1997, now U.S. Pat. No. 6,069,260, which is adivisional application of U.S. Ser. No. 08/483,309, filed Jun. 7, 1995,now U.S. Pat. 5,723,634, which is a continuation application of U.S.Ser. No. 08/314,532, filed Sep. 28, 1994, now U.S. Pat. No. 5,466,834,which is a continuation-in-part application of U.S. Ser. No. 07/949,107,filed Sep. 22, 1992, now abandoned, which is a continuation-in-partapplication of U.S. Ser. No. 07/863,849, filed Apr. 6, 1992, nowabandoned, which is a continuation-in-part application of U.S. SerialNo. 07/862,955, filed Apr. 3, 1992, now abandoned, which is acontinuation-in-part application of U.S. Ser. No. 07/763,805, filed Sep.23,1991, now abandoned.

This invention was made with Government support under NIH Grant #CA42031 and NIH Grant #CA 55131 awarded by the National Institutes ofHealth. The Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Three esters of N-acyl phenyl isoserine, taxol, taxotere andcephaloniannine have been found to possess significant properties, asantitumor agents. This application describes a process for thepreparation of N-acyl, N-sulfonyl and N-phosphoryl substituted isoserineesters, in general and to a semi-synthesis for the preparation of taxanederivatives such as taxol, taxotere and other biologically activederivatives involving the use of metal alkoxides and β-lactams, inparticular.

The Laxane family of terpenes, of which taxol is a member, has attractedconsiderable interest in both the biological and chemical arts. Taxol isa promising cancer chemotherapeutic agent with a broad spectrum ofantileukemic and tumor-inhibiting activity. Taxol has the followingstructure:

wherein Ph is phenyl and Ac is acetyl. Because of this promisingactivity, taxol is currently undergoing clinical trials in both Franceand the United States.

The supply of taxol for these clinical trials is presently beingprovided by the bark from Taxus brevifollia (Western Yew). However,taxol is found only in minute quantities in the bark of these slowgrowing evergreens, causing considerable concern that the limited supplyof taxol will not meet the demand. Consequently, chemists in recentyears have expended their energies in trying to find a viable syntheticroute for the preparation of taxol. So far, the results have not beenentirely satisfactory.

One synthetic route that has been proposed is directed to the synthesisof the tetracyclic taxane nucleus from commodity chemicals. A synthesisof the taxol congener taxusin has been reported by Holton, et al. inJACS 110, 6558 (1988). Despite the progress made in this approach, thefinal total synthesis of taxol is, nevertheless, likely to be amulti-step, tedious, and costly process.

A semi-synthetic approach to the preparation of taxol has been describedby Greene, et al. in JACS 110, 5917 (1988), and involves the use of acongener of taxol, 10-deacetyl baccatin III which has the structure offormula II shown below:

10-deacetyl baccatin III is more readily available than taxol since itcan be obtained from the needles of Taxus baccata. According to themethod of Greene et al., 10-deacetyl baccatin III is converted to taxolby attachment of the C-10 acetyl group and by attachment of tile C-13β-amido ester side chain through the esterification of the C-13 alcoholwith a β-amido carboxylic acid unit. Although this approach requiresrelatively few steps, the synthesis of the β-amido carboxylic acid unitis a multi-step process which proceeds in low yield, and the couplingreaction is tedious and also proceeds in low yield. However, thiscoupling reaction is a key step which is required in every contemplatedsynthesis of taxol or biologically active derivative of taxol, since ithas been shown by Wani, et al. in JACS 93, 2325 (1971) that the presenceof the β-amido ester side chain at C13 is required for anti-tumoractivity.

More recently, it has been reported in Colin et al. U.S. Pat. No.4,814,470 that taxol derivatives of the formula III below, have anactivity significantly greater than that of taxol (I).

R′ represents hydrogen or acetyl and one of R″ and R′″ representshydroxy and the other represents tert-butoxy-carbonylamino and theirstereoisomeric forms, and mixtures thereof.

According to Colin et al., U.S. Pat. No. 4,418,470, the products ofgeneral formula (III) are obtained by the action of the sodium salt oftert-butyl N-chlorocarbamate on a product of general formula:

in which R′ denotes an acetyl or 2,2,2-trichloroethoxycarbonyl radical,followed by the replacement of the 2,2,2-trichloroethoxycarbonyl groupor groups by hydrogen. It is reported by Denis et al. in U.S. Pat. No.4,924,011, however, that this process leads to a mixture of isomerswhich has to be separated and, as a result, not all the baccatin III or10-deactylbaccatin III employed for the preparation of the product ofgeneral formula (IV) can be converted to a product of general formula(III).

In an effort to improve upon the Colin et al. process, Denis et al.disclose a different process for preparing derivatives of baccatin IIIor of 10-deactylbaccatin III of general formula

in which R′ denotes hydrogen or acetyl wherein an acid of generalformula:

in which R₁ is a hydroxy-protecting group, is condensed with a taxanederivative of general formula:

in which R₂ is an acetyl hydroxy-protecting group and R₃ is ahydroxy-protecting group, and the protecting groups R₁, R₃ and, whereappropriate, R₂ are then replaced by hydrogen. However, this methodemploys relatively harsh conditions, proceeds with poor conversion, andprovides less than optimal yields.

A major difficulty remaining in the synthesis of taxol and otherpotential anti-tumor agents is the lack of a readily available methodfor easy attachment, to the C-13 oxygen, of the chemical unit whichprovides the β-amido ester side chain. Development of such a process forits attachment in high yield would facilitate the synthesis of taxol aswell as related anti-tumor agents having a modified set of nuclearsubstituents or a modified C-13 side chain. This need has been fulfilledby the discovery of a new, efficient process for attachment, to the C-13oxygen, of the chemical unit which provides the β-amido ester sidechain.

Another major difficulty encountered in the synthesis of taxol is thatknown processes for the attachment of the β-amido ester side chain atC-13 are generally not sufficiently diastereoselective. Therefore theside chain precursor must be prepared in optically active form to obtainthe desired diastereomer during attachment. The process of thisinvention, however, is highly diastereoselective, thus permitting theuse of a racemic mixture of side chain precursor, eliminating the needfor the expensive, time-consuming process of separating the precursorinto its respective enantiomeric forms. The reaction additionallyproceeds at a faster rate than previous processes, thus permitting theuse of less side-chain precursor than has been required by such previousprocesses.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof a process for the preparation of N-acyl, N-sulfonyl and N-phosphorylesters of isoserine; the provision of a side chain precursor for thesynthesis of taxane derivatives; the provision of a process for theattachment of the side chain precursor in relatively high yield toprovide an intermediate which is readily converted to the desired taxanederivative; and the provision of such a process which is highlydiastereoselective.

In accordance with the present invention, a process is provided for thepreparation of isoserine esters having the formula

comprising reacting a β-lactam with a metal alkoxide, the β-lactamhaving the formula

and the metal alkoxide having the formula

MOCE₁E₂E₃

wherein

R₁ is —OR₆, —SR₇, or —NR₈R₉;

R₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

R₃ and R₄ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, or acyl, provided, however, that R₃ and R₄ are not bothacyl;

R₅ is —COR₁₀, —COOR₁₀, —COSR₁₀, —CONR₈R₁₀, —SO₂R₁₁, or —POR₁₂R₁₃,

R₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyprotecting group, or a functional group which increases the watersolubility of the taxane derivative,

R₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group,

R₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

R₉ is an amino protecting group;

R₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl,

R₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OR₁₀, or —NR₈R₁₄,

R₁₂ and R₁₃ are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl,—OR₁₀, or —NR₈R₁₄,

R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

E₁, E₂ and E₃ are independently hydrogen, hydrocarbon or cyclic,provided, at least one of E₁, E₂ and E₃ is other than hydrogen.Preferably, two of E₁, E₂₁ and E₃ together with the carbon to which theyare attached comprise a mono- or polycyclic skeleton.

In accordance with another aspect of the present invention, the metalalkoxide and B-lactam are selected so as to provide a process forpreparing taxol, taxotere and other biologically active taxanederivatives having the following structural formula:

wherein

R₁-R₁₄ are as previously defined,

R₁₅ and R₁₆ are independently hydrogen, hydroxy, lower alkanoyloxy,alkenoyloxy, alkynoyloxy, aryloyloxy or R₁₅ and R₁₆ together form anoxo;

R₁₇ and R₁₈ are independently hydrogen or lower alkanoyloxy,alkenoyloxy, alkynoyloxy, or aryloyloxy or R₁₇ and R₁₈ together form anoxo;

R₁₉ and R₂₀ are independently hydrogen or hydroxy or lower alkanoyloxy,alkenoyloxy, alkynoyloxy, or aryloyloxy;

R₂₁ and R₂₂ are independently hydrogen or lower alkanoyloxy,alkenoyloxy, alkynoyloxy, or aryloyloxy or R₂₁ and R₂₂ together form anoxo;

R₂₄ is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy,alkynoyloxy, or aryloyloxy; or

R₂₃ and R₂₄ together form an oxo or methylene or

R₂₃ and R₂₄ together with the carbon atom to which they are attachedform an oxirane ring or

R₂₃ and R₂₂ together with the carbon atom to which they are attachedform an oxetane ring;

R₂₅ is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy,alkynoyloxy, or aryloyloxy or

R₂₆ is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy,alkynoyloxy, or aryloyloxy; or R₂₆ and R₂₅ taken together form an oxo;and

R₂₇ is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, or aryloyloxy.

Briefly, therefore, the taxane derivatives are prepared by reacting aβ-lactam (2) with a metal alkoxide having the bi-, tri- or tetracyclictaxane nucleus to form a β-amido ester intermediate. The intermediate isthen converted to the taxane derivative. β-lactam (2) has the generalformula:

wherein R₁-R₅ are as previously defined. The metal alkoxide preferablyhas the tricyclic taxane nucleus corresponding to the general formula:

wherein M is a metal, and R₁₅-R₂₇ are as previously defined. Mostpreferably, the metal alkoxide has the tetracyclic taxane nucleuscorresponding to metal alkoxide (3) wherein R₂₂ and R₂₃ together form anoxetane ring.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION

The present invention is directed to a process for preparing substitutedisoserine esters, in general, and taxol, taxotere and other taxanederivatives which are biologically active using β-lactam (2), thestructure of which is depicted hereinbelow:

wherein R₁, R₂, R₃, R₄ and R₅ are as previously defined.

In accordance with the present invention, R₅ of β-lactarn (2) ispreferably —COR₁₀ with R₁₀ with R₁₀ being aryl, heteroaryl,p-substituted phenyl, or lower alkoxy, and most preferably phenyl,methoxy, ethoxy, tert-butoxy (“tBuO”; (CH₃)₃CO—), or

wherein X is Cl, Br, F, CH₃O—, or NO₂—. Preferably R₂ and R₄ arehydrogen or lower alkyl. R₃ is preferably aryl, most preferably,naphthyl, phenyl,

wherein X is as previously defined, Me is methyl and Ph is phenyl.Preferably, R₁ is selected from —OR₆, —SR₇ or —NR₈R₉ wherein R₆, R₇ andR₉, are hydroxy, sulfhydryl, and amine protecting groups, respectively,and R₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl. Mostpreferably, R₁ is —OR₆ wherein R₆ is triethylsilyl (“TES”),1-ethoxyethyl (“EE”) or 2,2,2-trichloroethoxymethyl.

The β-lactam alkyl groups, either alone or with the various substituentsdefined hereinabove are preferably lower alkyl containing from one tosix carbon atoms in the principal chain and up to 15 carbon atoms. Theymay be straight or branched chain and include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.

The β-lactam alkenyl groups, either alone or with the varioussubstituents defined hereinabove are preferably lower alkenyl containingfrom two to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be straight or branched chain and include ethenyl,propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.

The β-lactam alkynyl groups, either alone or with the varioussubstituents defined hereinabove are preferably lower alkynyl containingfrom two to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be straight or branched chain and include ethynyl,propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.

The β-lactam aryl moieties described, either alone or with varioussubstituents, contain from 6 to 15 carbon atoms and include phenyl,α-naphthyl or β-naphthyl, etc. Substituents include alkanoxy, protectedhydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino,amido, etc. Phenyl is the more preferred aryl.

As noted above, R₁ of β-lactam (2) may be —OR₆ with R₆ being alkyl,acyl, ethoxyethyl (“EE”), triethylsilyl (“TES”),2,2,2-trichloroethoxymethyl, or other hydroxyl protecting group such asacetals and ethers, i.e., methoxymethyl (“MOM”), benzyloxymethyl;esters, such as acetates; carbonates, such as methyl carbonates; andalkyl and aryl silyl such as triethylsilyl, trimethylsilyl,dimethyl-t-butylsilyl, dimethylarylsilyl, dimethylheteroarylsilyl, andtriisopropylsilyl, and the like. A variety of protecting groups for thehydroxyl group and the synthesis thereof may be found in “ProtectiveGroups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981.The hydroxyl protecting group selected should be easily removed underconditions that are sufficiently mild, e.g., in 48% HF, acetonitrile,pyridine, or 0.5% HCl/water/ethanol, and/or zinc, acetic acid so as notto disturb the ester linkage or other substituents of the taxolintermediate. However, R₆ is preferably triethylsilyl, 1-ethoxyethyl or2,2,2-trichloroethoxymethyl, and most preferably triethylsilyl.

Also as noted previously, R₇ may be a sulfhydryl protecting group and R₉may be an amine protecting group. Sulfhydryl protecting groups includehemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, orthiocarbonates. Amine protecting groups include carbamates, for example,2,2,2-trichloroethylcarbamate or tertbutylcarbamate. A variety ofsulfhydryl and amine protecting groups may be found in theabove-identified text by T. W. Greene.

Since β-lactam (2) has several asymmetric carbons, it is known to thoseskilled in the art that the compounds of the present invention havingasymmetric carbon atoms may exist in diastereomeric, racemic, oroptically active forms. All of these forms are contemplated within thescope of this invention. More specifically, the present inventionincludes enantiomers, diastereomers, racemic mixtures, and othermixtures thereof.

β-lactam (2) can be prepared from readily available materials, as isillustrated in schemes A and B below:

reagents: (a) triethylamine, CH₂Cl₂, 25° C., 18 h; (b) 4 equiv cericammonium nitrate, CH₃CN, −10° C., 10 min; (c) KOH, THF, H₂O, 0° C., 30min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), 0° C.,1.5 h; (e) n-butyllithium, ether, −78° C., 10 min; benzoyl chloride,−78° C., 1 h; (f) lithium diisopropyl amide, THF −78° C. to −50° C.; (g)lithium hexamethyldisilazide, THF −78° C. to 0° C.; (h) THF, −78° C. to25° C., 12 h.

The starting materials are readily available. In scheme A, α-acetoxyacetyl chloride is prepared from glycolic acid, and, in the presence ofa tertiary amine, it cyclocondenses with imines prepared from aldehydesand p-methoxyaniline to give1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenylgroup can be readily removed through oxidation with ceric ammoniumnitrate, and the acyloxy group can be hydrolyzed under standardconditions familiar to those experienced in the art to provide3-hydroxy-4-arylazetidin-2-ones. The 3-hydroxyl group is protected with1-ethoxyethyl, but may be protected with variety of standard protectinggroups such as the triethylsilyl group or other trialkyl (or aryl) silylgroups. In Scheme B, ethyl-α-triethylsilyloxyacetate is readily preparedfrom glycolic acid.

The racemic β-lactams may be resolved into the pure enantiomers prior toprotection by recrystallization of the corresponding2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reactiondescribed hereinbelow in which the β-amido ester side chain is attachedhas the advantage of being highly diastereo-selective, thus permittingthe use of a racemic mixture of side chain precursor.

The 3-(1-ethoxyethoxy)-4-phenylazetidin-2-one of scheme A and the3-(1-triethylsilyloxy)-4-phenylazetidin-2-one of scheme B can beconverted to β-lactam (2), by treatment with a base, preferablyn-butyllithium, and an acyl chloride, alkylchloroformate, sulfonylchloride, phosphinyl chloride or phosphoryl chloride at −78° C. orbelow.

The process of the present invention is particularly useful for theesterification of mono- or polycyclic metal alkoxides which arerepresented by the formula

in which E₁, E₂ and the carbon to which they are attached define acarbocyclic and/or heterocyclic skeleton which may be mono- orpolycyclic and E₃ is hydrogen or hydrocarbon, preferably lower alkyl.Most preferably, the carbocyclic and/or heterocyclic skeleton comprisesabout 6 to 20 atoms and the hetero atoms are oxygen. The cyclic skeletonmay be hydrocarbon and/or heterosubstituted with heterosubstituentsincluding, for example, esters, ethers, amines, alcohols, protectedalcohols, carbonyl groups, halogens, oxygen, substituted oxygen orsubstituted nitrogen.

When the metal alkoxides have the bi-, tri- or tetracyclic taxanenucleus, the process of the present invention may advantageously be usedto prepare taxane derivatives, many of which have been found to havesignificant biological activity. As used herein, a metal alkoxide havingthe bicyclic taxane nucleus has the carbocyclic skeleton correspondingto rings A and B of metal alkoxide (3):

M and R₁₅-R₂₇ are as previously defined. A metal alkoxide having thetricyclic taxane nucleus has the carbocyclic skeleton corresponding torings A, B and C of metal alkoxide (3). A metal alkoxide having thetetracyclic taxane nucleus has carbocyclic rings A, B and C of metalalkoxide (3) and the oxetane ring defined by R₂₂, R₂₃, and the carbonsto which they are attached.

Preferably, the metal alkoxide used in the process of the presentinvention is metal alkoxide (3). Most preferably, R₁₅ is —OT₂ or—OCOCH₃; R₁₆ is hydrogen; R₁₇ and R₁₈ together form an oxo; R₁₉ is —OT₁;R₂₀ and R₂₁ are hydrogen; R₂₂ and R₂₃ together with the carbons to whichthey are attached form an oxetane ring; R₂₄ is CH₃COO—; R₂₅ is PhCOO—;R₂₆ is hydrogen; R₂₇ is hydroxy; and T₁ and T₂ are independentlyhydrogen or hydroxy protecting group.

Metal substituent, M, of metal alkoxide (3) is a Group IA, IIA, IIIA,lanthanide or actinide element or a transition, Group IIIA, IVA, VA orVIA metal. Preferably, it is a Group IA, IIA or transition metal, andmost preferably, it is lithium, magnesium, sodium, potassium ortitantium.

The metal alkoxide alkyl groups, either alone or with the varioussubstituents defined hereinabove are preferably lower alkyl containingfrom one to six carbon atoms in the principal chain and up to 10 carbonatoms. They may be straight or branched chain and include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and thelike.

The metal alkoxide alkenyl groups, either alone or with the varioussubstituents defined hereinabove are preferably lower alkenyl containingfrom two to six carbon atoms in the principal chain and up to 10 carbonatoms. They may be straight or branched chain and include ethenyl,propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.

The metal alkoxide alkynyl groups, either alone or with the varioussubstituents defined hereinabove are preferably lower alkynyl containingfrom two to six carbon atoms in the principal chain and up to 10 carbonatoms. They may be straight or branched chain and include ethynyl,propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.

Exemplary alkanoyloxy include acetate, propionate, butyrate, valerate,isobutyrate and the like. The more preferred alkanoyloxy is acetate.

The metal alkoxide aryl moieties, either alone or with varioussizbstituents contain from 6 to 10 carbon atoms and include phenyl,α-naphthyl or β-naphthyl, etc. Substituents include alkanoxy, hydroxy,halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc.Phenyl is the more preferred aryl.

Metal alkoxides (3) are prepared by reacting an alcohol having two tofour rings of the taxane nucleus and a C-13 hydroxyl group with anorganometallic compound in a suitable solvent. Preferably, the alcoholis a derivative of baccatin III or 10-deacetyl baccatin III having thestructure

wherein T₁ is a hydroxy protecting group, and Z is —OT₂ wherein T₂ isacyl, preferably acetyl, or other hydroxy protecting group. Mostpreferably, the alcohol is a protected baccatin III, in particular,7-O-triethylsilyl baccatin III (which can be obtained as described byGreene, et al. in JACS 110, 5917 (1988) or by other routes) or7,10-bis-O-triethylsilyl baccatin III.

As reported in Greene et al., 10-deacetyl baccatin III is converted to7-O-triethylsilyl-10-deacetyl baccatin III according to the followingreaction scheme:

Under what is reported to be carefully optimized conditions, 10-deacetylbaccatin III is reacted with 20 equivalents of (C₂H₅)₃SiCl at 23° C.under an argon atmosphere for 20 hours in the presence of 50 ml ofpyridine/mmol of 10-deacetyl baccatin III to provide7-triethylsilyl-10-deacetyl baccatin III (6a) as a reaction product in84-86% yield after purification. The reaction product is then acetylatedwith 5 equivalents of CH₃COCl and 25 mL of pyridine/mmol of (6a) at 0°C. under an argon atmosphere for 48 hours to provide 86% yield of7-O-tri-ethylsilyl baccatin III (6b). Greene, et al. in JACS 110, 5917at 5918 (1988).

Alternatively, 7-triethylsilyl-10-deacetyl baccatin III (6a) can beprotected at C-10 oxygen with an acid labile hydroxyl protecting group.For example, treatment of (6a) with n-butyllithium in THF followed bytriethylsilyl chloride (1.1 mol equiv.) at 0° C. gives7,10-bis-O-triethylsilyl baccatin III (6c) in 95% yield. Also, (6a) canbe converted to 7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (6d)in 90% yield by treatment with excess ethyl vinyl ether and a catalyticamount of methane sulfonic acid. These preparations are illustrated inthe reaction scheme below.

7-O-triethylsilyl baccatin III (6b), 7,10-bis-O-triethylsilyl baccatinIII (6c), or 7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (6d) isreacted with an organometallic compound such as n-butyllithium in asolvent such as tetrahydrofuran (THF), to form the metal alkoxide13-O-lithium-7-O-triethylsilyl baccatin III (7b)13-O-lithium-7,10-bis-O-triethylsilyl baccatin III (7c), or13-O-lithium-7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (7d) asshown in the following reaction scheme:

As illustrated in the following reaction scheme, a suitable metalalkoxide of the present invention such as 13-O-lithium-7-O-triethylsilylbaccatin III derivative (7b, 7c, or 7d) reacts with a β-lactam of thepresent invention to provide an intermediate (8b, 8c, 8d), in which theC-7 hydroxyl group is protected with a triethylsilyl or 1-ethoxyethylgroup.

Intermediate compound (8b) readily. converts to taxol when R₁ is —OR₆,R₂ and R₃ are hydrogen, R₄ is phenyl, R₅ is benzoyl and R₆ is a hydroxyprotecting group such as triethylsilyl. Intermediate compound (8c)readily converts to taxotere when R₁ is —OR₆, R₂ and R₃ are hydrogen, R₄is phenyl, R₅ is tertbutoxycarbonyl and R₆ is a hydroxy protecting groupsuch as triethylsilyl. Intermediate compound (8d) readily converts to10-deacetyl taxol when R₁ is —OR₆, R₂ and R₃ are hydrogen, R₄ is phenyl,R₅ is benzoyl, and R₆ is a hydroxy protecting group such astriethylsilyl. Intermediate compounds (8b, 8c and 8d) may be convertedto the indicated compounds by hydrolyzing the triethylsilyl and1-ethoxyethyl groups under mild conditions so as not to disturb theester linkage or the taxane derivative substituents.

Other taxane derivatives may readily be prepared by selection of theproper substituents R₁-R₅ of β-lactam (2) or R₁₅-R₂₇ of metal alkoxide(3). The preparation of such other compounds is illustrated in theexamples which follow.

Both the conversion of the alcohol to the metal alkoxide and theultimate synthesis of the taxol can take place in the same reactionvessel. Preferably, the β-lactam is added to the reaction vessel afterformation therein of the metal alkoxide.

The organometallic compound n-butyllithium is preferably used to convertthe alcohol to the corresponding metal alkoxide, but other sources ofmetallic substituent such as lithium diisopropyl amide, other lithium ormagnesium amides, ethylmagnesium bromide, methylmagnesium bromide, otherorganolithium compounds, other organomagnesium compounds, organosodium,organotitanium, organozirconium, organozinc, organocadmium ororganopotassium or the corresponding amides may also be used.Organometallic compounds are readily available, or may be prepared byavailable methods including reduction of organic halides with metal.Lower alkyl halides are preferred. For example, butyl bromide can bereacted with lithium metal in diethyl ether to give a solution ofn-butyllithium in the following manner:

Alternatively, the lithium alkoxide may be induced to undergo exchangewith metal halides to form alkoxides of aluminum, boron, cerium,calcium, zirconium or zinc.

Although THF is the preferred solvent for the reaction mixture, otherethereal solvents, such as dimethoxyethane, or aromatic solvents mayalso be suitable. Certain solvents, including some halogenated solventsand some straight-chain hydrocarbons in which the reactants are toopoorly soluble, are not suitable. Other solvents are not appropriate forother reasons. For example, esters are not appropriate for use withcertain organometallic compounds such as n-butyllithium due toincompatibility therewith.

Although the reaction scheme disclosed herein is directed to thesynthesis of certain taxol derivatives, it can be used withmodifications in either the β-lactam or the tetracyclic metal alkoxide.Therefore metal alkoxides other than 13-O-lithium-7-O-triethylsilylbaccatin III may be used to form a taxol intermediate according to themethod of this invention. The β-lactam and the tetracyclic metalalkoxide can be derived from natural or unnatural sources, to prepareother synthetic taxols, taxol derivatives, 10-deacetyltaxols, and theenantiomers and diastereomers thereof contemplated within the presentinvention.

The process of the invention also has the important advantage of beinghighly diastereoselective. Therefore racemic mixtures of the side chainprecursors may be used. Substantial cost savings may be realized becausethere is no need to resolve racemic β-lactams into their pureenantiomers. Additional cost savings may be realized because less sidechain precursor, e.g., 60-70% less, is required relative to priorprocesses.

The water solubility of compounds of formula (1) may be improved if R₁is —OR₆ and R₁₉ is —OT₁, and R₆ and/or T₁ are a functional group whichincreases solubility, such as —COGCOR¹ wherein

G is ethylene, propylene, CHCH, 1,2-cyclohexane, or 1,2-phenylene,

R¹=OH base, NR²R³, OR³, SR³, OCH₂CONR⁴R⁵, OH

R²=hydrogen, methyl

R³=(CH₂)_(n)NR⁶R⁷; (CH₂)_(n)N^(⊕)R⁶R⁷R⁸X₁ ^(⊖)

n=1 to 3

R⁴=hydrogen, lower alkyl containing 1 to 4 carbons

R⁵=hydrogen, lower alkyl containing 1 to 4 carbons, benzyl,hydroxyethyl, CH₂CO₂H, dimethylaminoethyl

R⁶R⁷=lower alkyl containing 1 or 2 carbons, benzyl or R⁶ and

R⁷ together with the nitrogen atom of NR⁶R⁷ form the following rings

R⁸=lower alkyl containing 1 or 2 carbons,benzyl

X₁ ^(⊖)=halide

base=NH₃, (HOC₂H₄)₃N, N(CH₃)₃, CH₃N(C₂H₄OH)₂, NH₂(CH₂)₆NH₂,N-methylglucamine, NaOH, KOH.

The preparation of compounds in which R₆ or T₁ is —COGCOR¹ is set forthin Hangwitz U.S. Pat. No. 4,942,184 which is incorporated herein byreference.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of 2′-Ethoxyethyl-7-triethylsilyl Taxol, andSubsequently Taxol, from Racemic β-lactam

To a solution of 7-triethylsilyl baccatin III (20 mg, 0.028 mmol) in 1ml of THF at −78° C. was added dropwise 0.17 ml of a 0.164M solution ofnBuLi in hexane. After 30 min at −78° C., a solution ofcis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (47.5 mg, 0.14mmol) in 1 ml of THF was added dropwise to the mixture. The solution wasallowed to slowly warm (over 1.5 h) to 0° C. and was then stirred at 0°C. for 1 h and 1 ml of a 10% solution of AcOH in THF was added. Themixture was partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by flash chromatography to give 23 mg (80%) of (2′R,3′S)-2′-ethoxyethyl-7-triethylsilyl taxol and 3.5 mg (13%) of2′,3′-epi(2′S, 3′R)-2′-ethoxyethyl-7-triethylsilyl taxol.

A 5 mg sample of (2′R, 3′S)-2′-ethoxyethyl-7-triethylsilyl taxol wasdissolved in 2 ml of ethanol, and 0.5 ml of 0.5% aqueous HCl solutionwas added. The mixture was stirred at 0° C. for 30 h and diluted with 50ml of ethyl acetate. The solution was extracted with 20 ml of saturatedaqueous sodium bicarbonate solution, dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography toprovide 4.5 mg (ca. 90%) taxol, which was identical with an authenticsample in all respects.

A 5 mg sample of 2′,3′-epi(2′S,3′R)-2′-ethoxyethyl-7-triethylsilyl taxolwas dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HCl solutionwas added. The mixture was stirred at 0° C. for 30 h and diluted with 50ml of ethyl acetate. The solution was extracted with 20 ml of saturatedaqueous sodium bicarbonate solution, dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography toprovide 4.5 mg (ca. 90%) of 2′,3′-epitaxol.

EXAMPLE 2 Preparation of 2′,7-(bis)Triethylsilyl Taxol, and SubsequentlyTaxol, from Racemic β-lactam

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1ml of THF at −45° C. was added dropwise 0.087 ml of a 1.63M solution ofnBuLi in hexane. After 1 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy)-4-phenylazetidin-2-one (274 mg, 0.715mmol) in 1 ml of THF was added dropwise to the mixture. The solution wasallowed to warm to 0° C. and held at 0° C. for 1 h. One ml of a 10%solution of AcOH in THF was added. The mixture was partitioned betweensaturated aqueous NAHCO₃ and 60/40 ethyl acetate/hexane. Evaporation ofthe organic layer gave a residue which was purified by flashchromatography followed by recrystallization to give 131 mg (85%) of(2′R, 3′S)-2′,7-(bis)triethylsilyl taxol and 15 mg (10%) of2′,3′-epi(2′S,3′R)-2′,7-(bis)triethylsilyl taxol.

To a solution of 121.3 mg (0.112 mmol) of (2′R,3′S)-2′,7-(bis)triethylsilyl taxol in 6 ml of acetonitrile and 0.3 ml ofpyridine at 0° C. was added 0.9 ml of 48% aqueous HF. The mixture wasstirred at 0° C. for 8 h, then at 25° C. for 6 h. The mixture waspartitioned between saturated aqueous sodium bicarbonate and ethylacetate. Evaporation of the ethyl acetate solution gave 113 mg ofmaterial which was purified by flash chromatography andrecrystallization to give 94 mg (98%) taxol, which was identical with anauthentic sample in all respects.

To a solution of 5 mg of (2R, 3S)-2′,7-(bis) triethylsilyl taxol in 0.5ml of acetonitrile and 0.03 ml of pyridine at 0° C. was added 0.09 ml of48% aqueous HF. The mixture was stirred at 0° C. for 8 h, then at 25° C.for 6 h. The mixture was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. Evaporation of the ethyl acetate solutiongave 5 mg of material which was purified by flash chromatography andrecrystallization to give 4.6 mg (ca. 95%) of 2′,3′-epitaxol.

EXAMPLE 3 Preparation of 2′,7-(bis)Triethylsilyl Taxol, and SubsequentlyTaxol, from Optically Active β-lactam

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1ml of THF at −45° C. was added dropwise 0.087 ml of a 1.63M solution ofnBuLi in hexane. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one (82 mg,0.215 mmol) in 1 ml of THF was added dropwise to the mixture. Thesolution was allowed to warm to 0° C. and held at 0° C. for 2 honors.One ml of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by flash chromatography followed by recrystallization togive 145 mg (94%) of (2′R, 3′S)-2′,7-(bis)triethylsilyl taxol.

To a solution of 121.3 mg (0.112 mmol) of (2′R,3′S)-2′,7-(bis)triethylsilyl taxol in 6 ml of acetonitrile and 0.3 ml ofpyridine at 0° C. was added 0.9 ml of 48% aqueous HF. The mixture wasstirred at 0° C. for 8 h, then at 25° C. for 6 h. The mixture waspartitioned between saturated aqueous sodium bicarbonate and ethylacetate. Evaporation of the ethyl acetate solution gave 113 mg ofmaterial which was purified by flash chromatography andrecrystallization to give 94 mg (98%) taxol, which was identical with anauthentic sample in all respects.

EXAMPLE 4 Preparation of Taxotere

To a solution of 7,10-bis-triethylsilyl baccatin III (200 mg, 0.248mmol)) in 2 mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63Msolution of nBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-(tert-butoxycarbonyl)-3-triethylsilyloxy-4-phenylazetidin-2-one(467 mg, 1.24 mmol) in 2 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 280 mg of crude2′,7,10-tris-triethylsilyl taxotere.

To a solution of 280 mg of the crude product obtained from the previousreaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0° C. wasadded 1.8 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 215 mg of material which was purified by flashchromatography to give 190 mg (95%) of taxotere, which wasrecrystallized from methanol/water. All analytical and spectral datawere identical with that reported for taxotere in U.S. Pat. No.4,814,470.

EXAMPLE 5

wherein N_(p2) is

Preparation of 3′-Desphenyl-3′-(2-naphthyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(2-naphthyl)azetidin-2-one (620 mg,1.43 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 320 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(2-naphthyl) taxol anda small amount of the (2′S,3′R) isomer.

To a solution of 320 mg (0.283 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 255 mg of material which was purified by flashchromatography to give 166 mg (64%) of 3′-desphenyl-3′-(2-naphthyl)taxol, which was recrystallized from methanol/water.

m.p 164-165° C.; [α]²⁵ _(Na) −52.6° (c 0.005, CHCl₃). ¹H NMR (CDCl₃, 300MHz) δ 8.14 (d, J=7.3 Hz, 2H, benzoate ortho), 7.96 (m, 1H, aromatic),7.90 (m, 1H, aromatic), 7.85 (m, 2H, aromatic), 7.76 (m, 2H, aromatic),7.60 (m, 3H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 2H, aromatic),7.01 (d, J=8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.26 (dd, J=9.2, 9.2 Hz,1H, H13), 5.97 (dd, J=8.8, 2.5 Hz, 1H, H3′), 5.68 (d, J=7.1 Hz, 1H,H2β), 4.93 (m, 1H, H5), 4.92 (m, 1H, H2′), 4.39 (m, 1H, H7), 4.30 (d,J=8.5 Hz, 1H, H20α), 4.20 (d, J=8.5 Hz, 1H, H20β), 3.81 (d, J=7.1 Hz,1H, H3), 3.60 (d, J=5 Hz, 1H, 2′OH), 2.48 (m, 1H, H6α), 2.45 (br, 1H,7OH), 2.39 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.83 (m,1H, H6β), 1.82 (br s, 3H, Me18), 1.68 (s, 1H, 10H), 1.68 (s, 3H, Me19),1.24 (s, 3H, Me17), 1.14 (s, 3H, Me16).

EXAMPLE 6

wherein N_(p1) is

Preparation of 3′-Desphenyl-3′-(1-naphthyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 g, 0.286 mmol) in 2ml of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane, After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(1-naphthylazetidin-2-one (620 mg,1.43 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NAHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 325 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(1-naphthyl) taxol anda small amount of the (2′S,3′R) isomer.

To a solution of 325 mg (0.287 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 ml of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then a 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 260 mg of material which was purified by flashchromatography to give 166 mg (64%) of 3′-(1-naphthyl) taxol, which wasrecrystallized from methanol/water.

m.p. 164-165° C.; [α]²⁵ _(NA) −52.6° (c 0.005, CHCl₃). ¹H NMR (CDCl₃,300 MHz) δ 8.11 (d, J=7.1 Hz, 2H, benzoate ortho), 8.11 (m, 3H,aromatic), 7.91 (m, 3H, aromatic), 7.70 (m, 2H, aromatic), 7.63-7.46 (m,7H, aromatic), 6.75 (d, J=8.8 Hz, 1H, NH), 6.52 (dd, J=8.8, 1.6 Hz, 1H,H3′), 6.27 (s, 1H, H10), 6.27 (dd, J=9.1, 9.1 Hz, 1H, H13), 5.68 (d,J=7.1 Hz, 1H, H2β), 4.85 (dd, J=7.6, 2.2 Hz, 1H, H5), 4.97 (dd, J=1.6Hz, 1H, H2′), 4.39 (m, 1H, H7), 4.24 (d, J=8.5 Hz, 1H, H20α), 4.17 (d,J=8.5 Hz, 1H, H20β), 3.80 (d, J=7.1 Hz, 1H, H3), 3.65 (br, 1H, 2′OH),2.55 (m, 1H, H6α), 2.48 (br, 1H, 7OH), 2.41 (s, 3H, 4Ac), 2.38 (m, 1H,H14), 1.96 (s, 3H, 10Ac), 1.86 (m, 1H, H6β), 1.80 (br s, 3H, Me18), 1.76(s, 1H, 10H), 1.69 (s, 3H, Me19), 1.28 (s, 3H, Me17), 1.16 (s, 3H,Me16).

EXAMPLE 7

Preparation of 3′-Desphenyl-3′-(4-methoxyphenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.114 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (590mg, 1.43 mmol) In 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 320 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(4-methoxyphenyl)taxol and a small amount of tho (2′S,3′R) isomer.

To a solution of 320 mg (0.288 mmol) of the mixture obtained from theprevious reaction in 13 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 ml, of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 255 mg of material which was purified by Clashchromatography to give 172 mg (68%) of 3′-desphenyl-3′-(4-methoxyphenyl)taxol, which was recrystallized from methanol/water.

m.p. 174-176° C.; [α]²⁵ _(Na) −48.86° (c 0.05, CHCl₃) ¹H NMR (CDCl₃, 300MHz) δ 8.12 (d, J=7.1 Hz, 2H, benzoate ortho), 7.72 (m, 2H, aromatic),7.59 (m, 1H, aromatic), 7.53-7.36 (m, 8H, aromatic), 6.96 (d, J=8.8 Hz,1H, NH), 6.90 (m, 2H, aromatic), 6.26 (s, 1H, H10), 6.21 (dd, J=9.3, 9.3Hz, 1H, H13), 5.70 (dd, J=8.8, 2.7 Hz, 1H, H3′), 5.56 (d, J=6.8 Hz, 1H,H2β), 4.93 (dd, J=9.9, 2.2 Hz, 1H, H5), 4.74 (dd, J=5.5, 2.7 Hz, 1H,H2′), 4.39 (m, 1H, H7), 4.29 (d, J=8.8 Hz, 1H, H20α), 4.18 (d, J=8.8 Hz,1H, H20β), 3.78 (d, J=6.8 Hz, 1H, H3), 3.78 (s, 3H, ArOMe), 3.67 (d,J=5.5 Hz, 1H, 2′OH), 2.61 (m, 1H, H6α), 2.50 (d, J=4.4 Hz, 1H, 7OH),2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.22 (s, 3H, 10Ac), 1.84 (m, 1H,H6β), 1.79 (br s, 3H, Me18), 1.79 (s, 1H, 1OH), 1.67 (s, 3H, Me19), 1.22(s, 3H, Me17), 1.13 (S, 3H, Me16).

EXAMPLE 8

Preparation of 3′-Desphonyl-3′-(4-chlorophenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.374 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(4-chlorophenyl)azetidin-2-one (595mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 320 mg of amixture containing (2′R,3′S)-2′,7-(bis)triethylsilyl3′-desphenyl-3′-(4-chlorophenyl) taxol and a small amount of the(2′S,3′R) isomer.

To a solution of 320 mg (0.287 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 255 mg of material which was purified by flashchromatography to give 158 mg (62%) of 3′-desphenyl-3′-(4-chlorophenyl)taxol, which was recrystallized from methanol/water.

m.p. 173-175° C.; [α]²⁵ _(Na)−50.8° (c 0.01, CHCl₃). ¹H NMR (CDCl₃, 300MHz) δ 8.13 (d, J=7.1 Hz, 2H, benzoate ortho), 7.72 (d, J=8.2 Hz, 2H,benzamide ortho), 7.65-7.35 (m, 10H, aromatic), 6.97 (d, J=3.8 Hz, 1H,NH), 6.27 (s, 1H, H10), 6.25 (dd, J=8.3, 8.3 Hz, 1H, H13), 5.78 (dd,J=8.8, 2.2 Hz, 1H, H3′), 5.67 (d, J=7.1 Hz, 1H, H2β), 4.95 (dd, J=8.8,2.2 Hz, 1H, H5), 4.77 (br s, 1H, H2′), 4.40 (m, 1H, H7), 4.31 (d, J=8.2Hz, 1H, H20α), 4.19 (d, J=8.2 Hz, 1H, H20β), 3.80 (d, 7.1 Hz, 1, H3),3.61 (br s, 1H, 2′OH), 2.54 (m, 1H, H6α), 2.38 (s, 3H, 4Ac), 2.32 (m,2H, H14), 2.24 (s, 3H, 10Ac), 1.85 (m, 1H, H6β), 1.80 (br s, 3H, Me18),1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16).

EXAMPLE 9

Preparation of 3′-Desphenyl-3′-(4-bromophenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.374 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(4-bromophenyl)azetidin-2-one (660mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 330 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-Desphenyl-3′-(4-bromophenyl) taxoland a small amount of the (2′S,3′R) isomer.

To a solution of 330 mg (0.284 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 265 mg of material which was purified by flashchromatography to give 186 mg (64%) of 3′-desphenyl-3′-(4-bromophenyl)taxol, which was recrystallized from methanol/water.

m.p. 170-172° C.; [α]²⁵ _(Na) −50.94° (c 0.01, CHCl₃). ¹H NMR (CDCl₃,300 MHz) δ 8.12 (d, J=7.2 Hz, 2H, benzoate ortho), 7.71 (m, 2H,aromatic), 7.61 (m, 1H, aromatic), 7.50-7.47 (m, 6H, aromatic), 7.38 (m,3H, aromatic), 7.04 (d, J=8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.23 (dd,J=8.2, 8.2 Hz, 1H, H13), 5.75 (dd, J=8.8, 2.2 Hz, 1H, H3′), 5.66 (d,J=7.1 Hz, 1H, H2β), 4.94 (dd, J=9.3, 1.7 Hz, 1H, H5), 4.75 (dd, J=2.2Hz, 1H, H2′), 4.38 (m, 1H, H7), 4.29 (d, J=8.2 Hz, 1H, H20α), 4.18 (d,J=8.2 Hz, 1H, H20β), 3.79 (d, J=7.1 Hz, 1H, H3), 3.7 (br, 1H, 2′OH),2.53 (m, 1H, H6α), 2.38 (br, 1H, 7OH), 2.37 (S, 3H, 4Ac), 2.30 (m, 2H,H14), 2.23 (s, 3H, 10AC), 1.87 (m, 1H, H6β), 1.80 (br s, 3H, Me18), 1.80(s, 1H, 1OH), 1.67 (s, 3H, Me19), 1.22 (s, 3H, Me17), 1.13 (s, 3H,Me16).

EXAMPLE 10

Preparation of 3′-Desphenyl-3′-(3,4-methylenedioxyphenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(3,4-methylenedioxyphenyl)azetidin-2-one(610 mg, 1.43 mmol) in 2 ml, of THF was added dropwise to the mixture.The solution was warned to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 320 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(3,4-methylenedioxyphenyl)taxol and a small amount of the (2′S,3′R) isomer.

To a solution of 320 mg (0.284 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 113 mg of material which was purified by flashchromatography to give 165 mg (64%) of3′-desphenyl-3′-(3,4-methylenedioxyphenyl) taxol, which wasrecrystallized from methanol/water.

m.p. 178-130° C.; [α]²⁵ _(Na) −46.6° (c 0.005, CHCl₃). ¹H NMR (CDCl₃,300 MHz) δ 8.14 (d, J=7.2 Hz, 2H, benzoate ortho), 7.72 (m, 2H,aromatic), 7.15 (m, 1H, aromatic), 7.50 (m, 2H, aromatic), 7.38 (m, 2H,aromatic), 7.0 (m, 1H, aromatic), 6.94 (m, 2H, aromatic), 6.88 (d, J=9.1Hz, 1H, NH), 6.83 (m, 1H, aromatic), 6.28 (s, 1H, H10), 6.23 (dd, J=9.1,9.1 Hz, 1H, H13), 5.97 (s, 2H, methylene), 5.69 (dd, J=9.1, 2.5 Hz, 1H,H3′), 5.68 (d, J=6.9 Hz, 1H, H2β), 4.95 (dd, J=9.6, 2.2 Hz, 1H, H5),4.72 (dd, J=2.5 Hz, 1H, H2′), 4.41 (m, 1H, H7), 4.31 (d, J=8.4 Hz, 1H,H20α), 4.20 (d, J=8.4 Hz, 1H, H20β), 3.81 (d, J=6.9 Hz, 1H, H3), 3.60(br, 1H, 2′OH), 2.56 (m, 1H, H6α), 2.43 (d, J=4.1 Hz, 1H, 7OH), 2.39 (s,3H, 4Ac), 2.31 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.88 (m, 1, H6β), 1.82(br s, 3H, Me18), 1.69 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.24 (s, 3H,Me17), 1.15 (5, 3H, Me16).

EXAMPLE 11

Preparation of 3′-Desphenyl-3′-(3,4-dimethoxyphenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of TIF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(3,4-dimethoxyphenyl)azetidin-2-one(630 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution or AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 330 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(3,4-dimethoxyphenyl)taxol and a small amount of the (2′S,3′R) isomer.

To a solution of 330 mg (0.286 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 260 mg of material which was purified by flashchromatography to give 175 mg (67%) of3′-desphenyl-3′-(3,4-dimethoxyphenyl) taxol, which was recrystallizedfrom methanol/water.

m.p. 165-167° C.; [α]²⁵ _(Na) −42.0° (c 0.005, CHCl₃). ¹H NM (CDCl₃, 300MHz) δ 8.12 (d, J=8.3 Hz, 2H, benzoate ortho), 7.73 (d, J=8.2 Hz, 2H,benzamide ortho), 7.65-7.35 (m, 6H, aromatic), 7.1-7.0 (m, 2H,aromatic), 6.94 (d, J=8.8 Hz, 1H, NH), 6.88 (d, J=8.3 Hz, 2H, aromatic),6.27 (s, 1H, H10), 6.21 (dd, J=9.3, 9.3 Hz, 1H, H13), 5.69 (m, 2H, H3,H2β), 4.94 (dd, Hz, J=9.9, 2.2 Hz, 1H, H5), 4.77 (d, J=2.8 Hz, 1H, H2′),4.39 (dd, J=11.0, 6.6 Hz, 1H, H7), 4.30 (d, J=8.5 Hz, 1H, H20α), 4.19(d, J=8.5 Hz, 1H, H20β), 3.88 (s, 3H, ArOMe), 3.87 (s, 3H, ArOMe), 3.80(d, J=7.1 Hz, 1H, H3), 3.59 (d, J=4.4 Hz, 1H, 2′OH), 2.54 (m, 1H, H6α),2.38 (s, 3H 4Ac), 2.36 (m, 2H, H14α, H14β), 2.23 (s, 3H, 10Ac), 1.86 (m,1H, H6β), 1.80 (br s, 3H, Me18), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17),1.14 (s, 3H, Me16).

EXAMPLE 12

Preparation of N-Debenzoyl-N-ethoxycarbonyl Taxol

To a solution of 7-triethylsilyl baccatin III (155 mg, 0. 221 mmol)) in2 mL of THF at −45° C. was added dropwise 0.136 mL of a 1.63M solutionof nBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-ethoxycarbonyl-3-triethylsilyloxy-4-phenylazetidin-2-one (386 mg,1.11 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 252 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-N-debenzoyl-N-ethoxycarbonyl taxol anda small amount of the (2′S,3′R) isomer.

To a solution of 252 mg (0.112 mmol) of the mixture obtained from theprevious reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0°C. was added 1.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 216 mg of material which was purified by flashchromatography to give 155 mg (85%) of N-debenzoyl-N-ethoxycarbonyltaxol, which was recrystallized from methanol/water.

m.p. 161.5-162.5° C.; [α]²⁵ _(Na) −62.2° (c 0.51, CHCl₃) ¹H NMR (CDCl₃,300 MHz) δ 8.12 (d, J=7.7 Hz, 2H, benzoate ortho), 7.65-7.3 (m, 8H,aromatic), 6.28 (m, 1H, H10) 6.27 (m, 1H, H13), 5.67 (d, J=7.1 Hz, 1H,H2β), 5.53 (d, J=9.3 Hz, 1H, H3′), 5.29 (d, J=9.3 Hz, 1H, NH), 4.94 (dd,J=9.3, 2.2 Hz, 1H, H5), 4.64 (dd, J=5.0, 2.8 Hz, 1H, H2′), 4.41 (m, 1H,H7), 4.29 (d, J=8.5 Hz, 1H, H20α), 4.17 (d, J=8.5 Hz, 1H, H20β), 4.01(q, J=7.1 Hz, 2H, COOCH₂CH₃), 3.79 (d, J=7.1 Hz, 1H, H3), 3.45 (d, J=5Hz, 1H, 2′OH), 2.54 (m, 1H, H6α), 2.47 (d, J=3.9 Hz 1H, 7OH), 2.36 (s,3H, 4Ac),2.24 (s, 3H, 10Ac), 2.22 (m, 2H, H14α, H14β), 1.87 (m, 1H,H6α), 1.83 (br s, 3H, Me18), 1.77 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.27(s, 3H, Me17), 1.15 (s, 3H, Me16), 1.14 (t, J=7.1 Hz, 2H, COOCH₂CH₃)

EXAMPLE 13

Preparation of 3′-Desphenyl-3′-(4-nitrophenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(4-nitrophenyl)azetidin-2-one (610mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warned to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 320 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(4-nitrophenyl) taxoland a small amount of the (2′S,3′R) isomer.

To a solution of 320 mg (0.284 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 255 mg of material which was purified by flashchromatography to give 147 mg (57%) of 3′-desphenyl-3′-(4-nitrophenyl)taxol, which was recrystallized from methanol/water.

m.p. 188-190° C.; [α]²⁵ _(Na) −63.7° (c 0.01, CHCl₃). ¹H NMR (CDCl₃, 300MHz) δ 8.26 (d, J=8.8 Hz, 2H, benzoate ortho), 8.20 (m, 2H, aromatic),7.73 (m, 4.1, aromatic), 7.60 (m, 1H, aromatic), 7.52 (m, 4H, aromatic),7.41 (m, 1H, aromatic), 7.15 (d, J=8.8 Hz, 1H, NH), 6.26 (s, 1H, H10),6.26 (dd, J=9.3, 9.3 Hz, 1H, H13), 5.93 (dd, J=8.8, 2.8 Hz, 1H, H3′),5.66 (d, J=6.6 Hz, 1H, H2β), 4.94 (dd, J=9.3, 1.7 Hz, 1H, H5), 4.82 (dd,J=3.9, 2.8 Hz, 1H, H2′), 4.38 (m, 1H, H7), 4.30 (d, J=8.8 Hz, 1H, H20α),4.19 (d, J=8.8 Hz, 1H, H20β), 3.86 (d, J=3.9 Hz, 1H, 2′OH), 3.79 (d,J=6.6 Hz, 1H, H3), 2.55 (m, 3H, H6α), 2.46 (d, J=3.8 Hz, 1H, 7OH), 2.41(s, 3H, 4Ac), 2.38 (m, 2H, H14), 2.23 (3, 3H, 10Ac), 1.82 (m, 1H, H6β),1.80 (br s, 3H, Me18), 1.74 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.21 (s,3H, Me17), 1.13 (s, 3H, Me16).

EXAMPLE 14

Preparation of 3′-Desphenyl-3′-(2-furyl) Taxol

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. was added dropwise 0.087 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(2-furyl)azetidin-2-one (266 mg,0.715 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 143 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(2-furyl) taxol and asmall amount of the (2′S,3′R) isomer.

To a solution of 143 mg of the mixture obtained from the previousreaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0° C. wasadded 0.9 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 115 mg of material which was purified by flashchromatography to give 98 mg (81%) of 3′-desphenyl-3′-(2-furyl) taxol,which was recrystallized from methanol/water.

m.p. 174-176° C.; [α]²⁵ _(Na) −47.8° (c 0.045, CHCl₃). ¹h NMR (CDCl₃,300 MHz) δ 8.14 (d, J=7.0 Hz, 2H, benzoate ortho), 7.74 (m, 2H,aromatic), 7.51 (m, 7H, aromatic), 6.86 (d, J=9.2 Hz, 1H, NH), 6.40 (d,J=1.2 Hz, 2H, furyl), 6.29 (s, 1H, H10), 6.24 (dd, J=9.2, 9.2 Hz, 1H,H13), 5.89 (dd, J=9.2, 2.4 Hz, 1H, H3′), 5.69 (d, J=7.0 Hz, 1H, H25),4.96 (dd, J=9.5, 1.8 Hz, 1H, H5), 4.83 (d, J=2.4 Hz, 1H, H2′), 4.42 (dd,J=10.7, 6.7 Hz, 1H, H7), 4.31 (d, J=8.6 Hz, 1H, H20α), 4.20 (d, J=8.6Hz, 1H, H20β), 3.83 (d, J=7.0 Hz, 1H, H3), 2.56 (m, 1H, H6α), 2.43 (s,3H, 4Ac), 2.35 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.89 (m, 1H, H6β), 1.87(br s, 3H, Me18), 1.87 (s, 1H, 1OH), 1.69 (s, 3H, Me19), 1.25 (5, 3H,Me17), 1.15 (s, 3H, Me16).

EXAMPLE 15

Preparation of 3′-Desphenyl-3′-(4-fluorophenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0. 286 mmol) in 2mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(4-florophenyl)azetidin-2-one (570mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 315 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(4-fluorophenyl) taxoland a small amount of the (2′S,3′R) isomer.

To a solution of 315 mg (0.286 mmol) of the mixture obtained from theprevious reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0°C. was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 250 mg of material which was purified by flashchromatography to give 160 mg (64%) of 3′-desphenyl-3′-(4-fluorophenyl)taxol, which was recrystallized from methanol/water.

m.p. 371-173° C.;[α]²⁵ _(Na) −49.0° (c 0.005, CHCl₃). ¹H NMR (CDCl₃, 300MHz) δ 8.13 (d, J=7.5 Hz, 2H, benzoate ortho), 7.25 (m, 2H, aromatic),7.61 (m, 1H, aromatic), 7.50 (m, 4H, aromatic), 7.43 (m, 2H, aromatic),7.10 (m, 2H, aromatic), 6.96 (d, J=8.7 Hz, 1H, NH), 6.27 (s, 1H, H10),6.25 (dd, J=8.7, 8.7 Hz, 1H, H13), 5.79 (dd, J=8.7, 2.4 Hz, 1H, H3′),5.67 (d, J=7.1 Hz, 1H, H2β), 4.45 (dd, J=7.9 Hz, in, H5), 4.76 (dd,J=4.8, 2.4 Hz, 1H, H2′), 4.39 (m, 1H, H7), 4.31 (d, J=8.9 Hz, 1H, H20α),4.20 (d, J=8.9 Hz, 1H, H20β), 3.80 (d, J=7.1 Hz, 1H, H3), 3.57 (d, J=4.8Hz, 1H, 2′OH), 2.58 (m, 1H, H6a), 2.43 (d, J=4.3 Hz, 1H, 7OH), 2.36 (s,3H, 4Ac), 2.30 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.85 (m, 1H, H6β), 1.80(br s, 3H, Me18), 1.69 (s, 1H, 1OH), 1.55 (s, 3H, Me19), 1.23 (s, 3H,Me17), 1.14 (s, 3H, Me16).

EXAMPLE 16

Preparation of 3′-Desphenyl-3′-(2-thienyl) Taxol

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. was added dropwise 0.087 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-(4-benzoyl)-3-triethylsilyloxy-4-(2-thienyl)azetidin-2-one (277mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 1 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 169 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-3′-desphenyl-3′-(2-thienyl) taxol anda small amount of the (2′S,3′R) isomer.

To a solution of 169 mg of the mixture obtained from the previousreaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0° C. wasadded 0.9 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 140 mg of material which was purified by flashchromatography to give 93 mg (76%) of 3′-desphenyl-3′-(2-thienyl) taxol,which was recrystallized from methanol/water.

m.p. 173-175° C.; [α]²⁵ _(Na)−42.1° (c 0.515, CHCl₃). ¹H NMR (CDCl₃, 300MHz) δ 8.14 (d, J=7.1 Hz, 2H, benzoate ortho), 7.72 (d, J=8.7 Hz, 2H,benzamide ortho), 7.65-7.35 (m, 6H, aromatic), 7.31 (dd, J=5.5, 1.1 Hz,1H, thienyl), 7.19 (dd, J=3.9, 1.1 Hz, 1H, thienyl), 7.03 (dd, J=5.5,3.9 Hz, 1H, thienyl), 6.96 (d, J=8.8 Hz, 1H, NH), 6.28 (s, 1H, H10),6.24 (dd, J=8.8, 7.7 Hz, H13), 6.05 (dd, J=8.3, 1.7 Hz, 1H, H3′), 5.68(d, J=7.1 Hz, 1H, H2), 4.95 (dd, J=9.3, 1.7 Hz, 1H, H5), 4.73 (d, J=2.2Hz, 1H, H2′), 4.40 (dd, J=11.0, 6.6 Hz, 1H, H7), 4.31 (d, J=8.5 Hz, 1H,H20α), 4.20 (d, J=8.05 Hz, 1H, H20β), 3.81 (d, J=7.1 Hz, 1H, H3), 3.72(br, s, 1H, 2′OH), 2.54 (m, 1H, H6α), 2.41 (s, 3H, 4Ac), 2.37 (m, 2H,H14α, H14β), 2.23 (s, 3H, 10Ac), 1.88 (m, 1H, H6α), 1.82 (br s, 3H,Me18), 1.68 (s, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16).

EXAMPLE 17 Preparation of 2′,7-3′-Hydroxy Protected Taxol UsingMagnesium Alkoxide

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. was added dropwise 0.048 mL of a 3.0 M solution ofmethyl magnesium bromide in ether. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one (82 mg,0.215 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 4 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by flash chromatography followed by recrystallization togive 148 mg (96%) of (2′R,3′S)-2′,7-(bis)triethylsilyl taxol.

EXAMPLE 18 Preparation of 2′,7-Hydroxy Protected Taxol Using PotassiumAlkoxide

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. was added dropwise 0.286 mL of a 0.5 M solution ofpotassium hexamethyldisilazide in toluene. After 1 h at −45° C., asolution of (+)-cis-1-benzoyl-3-triethylsilyloxy-4-phenyl-azetidin-2-one(82 mg, 0.215 mmol) in 1 mL of THF was added dropwise to tile mixture.The solution was warmed to 0° C. and kept at that temperature for 3 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by flash chromatography followed by recrystallization togive 139 mg (90%) of (2′R,3′S)-2′,7-(bis)triethylsilyl taxol.

EXAMPLE 19 Preparation of 2′,7-Hydroxy Protected Taxol Using LithiumAlkoxide From Lithium Hexamethyldisilazide

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. was added dropwise 0.143 mL of a 1.0 M solution oflithium hexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one (82 mg,0.215 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by flash chromatography followed by recrystallization togive 151 mg (98%) of (2′R,3′S)-2′,7-(bis)triethylsilyl taxol.

EXAMPLE 20 Preparation of Taxol Using Lithium Alkoxide (From LithiumHexamethyldisilazide)

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. was added dropwise 0.143 mL of a 1.0 M solution oflithium hexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by recrystallization to give 147 mg (99%) of(2′R,3′S)-2′-(2-methoxy-2-propyloxy)-7-triethylsilyl taxol.

To a solution of 116 mg (0.112 mmol) of(2R,3′S)-2′-(2-methoxy-2-propyloxy)-7-triethylsilyl taxol in 6 mL ofacetonitrile and 0.3 mL of pyridine at 0° C. was added 0.9 mL of 48%aqueous HF. The mixture was stirred at 0° C. for 8 h, then at 25° C. for10 h. The mixture was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. Evaporation of the ethyl acetate solutiongave 113 mg of material which was purified by recrystallization to give95 mg (99%) of taxol, which was identical with an authentic sample inall respects.

EXAMPLE 21 Menthyl N-Benzoyl-(2′R,3′S)-phenylisoserine Ester

To a solution of (−)-menthol (22 mg, 0.143 mmol) in 1 mL of THF at −45°C. was added dropwise 0.143 mL of a 1.0 M solution of lithiumhexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave 77 mg of a residuewhich was dissolved in 6 mL of THF at 0° C. To this solution was added0.9 mL of glacial acetic acid and 0.9 mL of water. The mixture wasstirred at 0° C. for 3 h, then partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 70 mg of material which was purified by chromatography onsilica gel to give 48 mg (80%) of methylN-benzoyl-(2′R,3′S)-phenylisoserine ester.

EXAMPLE 22 Bornyl N-Benzoyl-(2′R,3′S)-phenylisoserine Ester

To a solution of (−)-borneol (22 mg, 0.143 mmol) in 1 mL of THF at −45°C. was added dropwise 0.143 mL of a 1.0 M solution of lithiumhexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to tile mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave 75 mg of a residuewhich was dissolved in 6 mL of THF at 0° C. To this solution was added0.9 mL of glacial acetic acid and 0.9 mL of water. The mixture wasstirred at 0° C. for 3 h, then partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 70 mg of material which was purified by chromatography onsilica gel to give 54 mg (90%) of bornylN-benzoyl-(2′R,3′S)-phenylisoserine ester.

EXAMPLE 23 S-verbenyl N-Benzoyl-(2′R,3′S)-phenylisoserine Ester

To a solution of S-cis-verbenol (22 mg, 0.143 mmol) in 1 mL of THF at−45° C. was added dropwise 0.143 mL of a 1.0 M solution of lithiumhexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave 79 mg of a residuewith was dissolved in 6 mL of THF at 0° C. To this solution was added0.9 mL of glacial acetic acid and 0.9 mL of water. The mixture wasstirred at 0° C. for 3 h, then partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 70 mg of material which was purified by chromatography onsilica gel to give 55 mg (92%) of S-verbenylN-benzoyl-(2′R,3′S)-phenylisoserine ester.

EXAMPLE 24 Terpinen-4-yl N-Benzoyl-(2′R,3′S)-phenylisoserine Ester

To a solution of (+)-terpinene-4-ol (22 mg, 0.143 mmol) in 1 mL of THFat −45° C. was added dropwise 0.143 mL of a 1.0 M solution of lithiumhexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave 80 mg of a residuewhich was dissolved in 6 mL of THF at 0° C. for 3 h, then partitionedbetween saturated aqueous sodium bicarbonate and ethyl acetate.Evaporation of the ethyl acetate solution gave 70 mg of material whichwas purified by chromatography on silica gel to give 50 mg (83%) ofterpinen-4-yl N-benzoyl-(2′R,3′S)-phenylisoserine ester.

EXAMPLE 25 Isopinocamphenyl N-benzoyl-(2′R,3′S)-phenyl-isoserine Ester

To a solution of (−)-isopinocamphenyl (22 mg, 0.143 mmol) in 1 mL of THFat −45° C. was added dropwise 0.143 mL of a 1.0 M solution of lithiumhexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave 77 mg of a residuewhich was dissolved in 6 mL of THF at 0° C. To this solution was added0.9 mL of glacial acetic acid and 0.9 mL of water. The mixture wasstirred at 0° C. for 3 h, then partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 70 mg of material which was purified by chromatography onsilica gel to give 53 mg (89%) of isocamphenylN-benzoyl-(2′R,3′S)-phenylisoserine ester.

EXAMPLE 26 α-Terpineyl N-Benzoyl-(2′R,3′S)-phenylisoserine Ester

To a solution of (−)-menthol (22 mg, 0.143 mmol) in 1 mL of THF at −45°C. was added dropwise 0.143 mL of a 1.0 M solution of lithiumhexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-(2-methoxy-2-propyloxy)-4-phenylazetidin-2-one (58mg, 0.172 mmol) in 1 mL of THF was added dropwise to the mixture. Thesolution was warmed to 0° C. and kept at that temperature for 2 h before1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ arid 60/40 ethylacetate/hexane. Evaporation of the organic layer gave 73 mg of a residuewhich was dissolved in 6 mL of THF at 0° C. To this solution was added0.9 mL of glacial acetic acid and 0.9 mL of water. The mixture wasstirred at 0° C. for 3 h, then partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 70 mg of material which was purified by chromatography onsilica gel to give 48 mg (80%) of α-terpineylN-benzoyl-(2′R,3′S)-phenylisoserine ester.

EXAMPLE 27 Preparation of 2′,7-Hydroxy Protected Taxol Using SodiumAlkoxide

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1mL of THF at −45° C. is added dropwise 0.143 mL of a 1 M solution ofsodium hexamethyldisilazide in THF. After 1 h at −45° C., a solution of(+)-cis-1-benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one (82 mg,0.215 mmol) in 1 mL of THF is added dropwise to the mixture. Thesolution is warmed to 0° C. and kept at that temperature for 3 h before1 mL of a 10% solution of AcOH in THF is added. The mixture ispartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gives a residue whichis purified by flash chromatography followed by recrystallization togive 108 mg (70%) of (2′R,3′S)-2′,7-(bis)triethylsilyl taxol.

EXAMPLE 28

Preparation of N-Debenzoyl-N-(4-chlorobenzoyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution of(+)-cis-1-(4-chlorobenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one(215 mg, 0.515 mmol) in 2 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 2 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 320 mg of crude(2′R,3′S)-2′,7-(bis)triethylsilyl-N-debenzoyl-N-(4-chlorobenzoyl) taxol.

To a solution of 320 mg (0.286 mmol) of this crude product in 18 mL ofacetonitrile and 0.93 mL of pyridine at 0° C. was added 2.8 mL of 48%aqueous HF. The mixture was stirred at 0° C. for 3 h, then at 25° C. for13 h, and partitioned between saturated aqueous sodium bicarbonate andethyl acetate. Evaporation of the ethyl acetate solution gave 252 mg ofmaterial which was purified by flash chromatography to give 213 mg (84%)of N-debenzoyl-N-(4-chlorobenzoyl) taxol, which was recrystallized frommethanol/water. m.p. 179-181° C.; [α]²⁵ _(Na) −49.8° (c 0.01, CHCl₃). ¹HNMR (CDCl₃, 300 MHz) δ 8.12 (d, J=7.1 Hz, 2H, benzoate ortho), 7.64 (m,2H, aromatic), 7.60 (m, 1H, aromatic), 7.49 (m, 9H, aromatic), 7.03 (d,J=8.8 Hz, 1H, NH), 6.26 (s, 1H, H10), 6.21 (dd, J=8.2, 8.2 Hz, 1H, H13),5.76 (dd, J=8.8, 2.2 Hz, 1H, H3′), 5.66 (d, J=7.1 Hz, 1H, H2β), 4.92(dd, J=9.9, 1.1 Hz, 1H, H5), 4.77 (dd, J=5.5, 2.2 Hz, 1H, H2′), 4.38 (m,1H, H7), 4.29 (d, J=8.8 Hz, 1H, H20α), 4.18 (d, J=8.5 Hz, 1H, H20β),3.78 (d, J=6.6 Hz, 1H, H3), 3.35 (d, J=5.5 Hz, 1H, 2′OH), 2.55 (m, 1H,H6α), 2.49 (d, J=4.2 Hz, 1H, 7OH), 2.36 (s, 3H, 4Ac), 2.28 (m, 2H, H14),2.22 (s, 3H, 10Ac), 1.85 (m, 1H, H6β), 1.77 (br s, 3H, Me18), 1.76 (s,1H, 1OH), 1.67 (s, 3H, Me19), 1.22 (s, 3H, Me17), 1.13 (s, 3H, Me16).

EXAMPLE 29

Preparation of N-Debenzoyl-M-(4-t-butylbenzoyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2mL of THF at −45° C. was added dropwise 0.174 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution of(+)-cis-1-(4-t-butylbenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one(226 mg, 0.515 mmol) In 2 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 2 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 330 mg of crude(2′R,3′S)-2′,7-(bis)triethylsilyl-N-debenzoyl-N-(4-t-butylbenzoyl)taxol.

To a solution of 330 mg (0.289 mmol) of this crude product in 18 mL ofacetonitrile and 0.93 mL of pyridine at 0° C. was added 2.8 mL of 48%aqueous HF. The mixture was stirred at 0° C. for 3 h, then at 25° C. for13 h, and partitioned between saturated aqueous sodium bicarbonate andethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg ofmaterial which was purified by flash chromatography to give 240 mg (92%)of N-debenzoyl-N-(4-t-butylbenzoyl) taxol, which was recrystallized frommethanol/water.

m.p. 171-173° C.; [α]²⁵ _(Na) −49.1° (c 0.05, CHCl₃). ¹H NMR (CDCl₃, 300MHz) δ 8.13 (d, J=7.1 Hz, 2H, benzoate ortho), 7.76-7.25 (m, 12H,aromatic), 6.98 (d, J=8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd,J=8.8, 8.8 Hz, 1H, H13), 5.77 (dd, J=8.8, 2.7 Hz, 1H, H3′), 5.67 (d,J=6.6 Hz, 1H, H2β), 4.94 (dd, J=9.3, 1.2 Hz, 1H, H5), 4.78 (dd, J=4.4,2.7 Hz, 1H, H2′), 4.38 (m, 1H, H7), 4.29 (d, J=8.2 Hz, 1H, H20α), 4.20(d, J=8.2 Hz, 1H, H20β), 3.79 (d, J=6.6 Hz, 1H, H3), 3.65 (d, J=4.4 Hz,1H, 2′OH), 2.57 (m, 1H, H6α), 2.48 (d, J=4.1 Hz, 1H, 7OH), 2.37 (s, 3H,4Ac), 2.31 (m, 2H, H14), 2.22 (s, 3H, 10Ac), 1.85 (m, 1H, H6β), 1.79 (brs, 3H, Me18), 1.68 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.29 (s, 9H,Ar^(t)Bu), 1.23 (s, 3H, Me17), 1.13 (s, 3H, Me16).

EXAMPLE 30

Preparation ofN-Debenzoyl-N-(4-methoxybenzoyl)-3′-desphenyl-3′-(4-fluorophenyl) Taxol

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2mL of THF at −45° C. was added dropwise 0.175 mL of a 1.63M solution ofnBuLi in hexane. After 0.5 h at −45° C., a solution ofcis-1-(4-methoxybenzoyl)-3-triethylsilyloxy-4-(4-fluorophenyl)azetidin-2-one(614 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 362 mg of amixture containing(2′R,3′S)-2′,7-(bis)triethylsilyl-N-debenzoyl-N-(4-methoxybenzoyl)-3′-desphenyl-3′-(4-fluorophenyl)taxol and a small amount of the (2′S,3′R) isomer.

To a solution of 362 mg of the mixture obtained from the previousreaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0° C. wasadded 1.8 mL of 48% aqueous HF. The mixture was stirred at 0° C. for 3h, then at 25° C. for 13 h, and partitioned between saturated aqueoussodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetatesolution gave 269 mg of material which was purified by flashchromatography to give 183 mg (71%) ofN-debenzoyl-N-(4-methoxybenzoyl)-3′-desphenyl-3′-(4-fluorophenyl) taxol,which was recrystallized from methanol/water.

m.p. 172.5-174.5° C.; [α]²⁵ _(Na) −47.0° (c 0.0044, CHCl₃). ¹H NMR(CDCl₃, 300 MHz) δ 8.13 (d, J=7.2 Hz, 2H, benzoate ortho), 7.7-7.4 (m,9H, aromatic), 7.10 (dd, J=8.8, 8.8 Hz, 2H, aromatic), 6.97 (d, J=8.8Hz, 1H, NH), 6.27 (s, 1H, H10), 6.23 (dd, J=8.8, 8.8 Hz, 1H, H13), 5.76(dd, J=8.8, 2.2 Hz, 1H, H3′), 5.67 (d, J=7.1 Hz, 1H, H2β), 4.94 (dd,J=9.9, 2.2 Hz, 1H, H5), 4.75 (dd, J=4.4, 2.2 Hz, 1H, H2′), 4.39 (m, 1H,H7), 4.31 (d, J=8.5 Hz, 1H, H20α), 4.19 (d, J=8.5 Hz, 1H, H20β), 3.79(d, J=7.1 Hz, 1H, H3), 3.59 (d, J=4.4 Hz, 1H, 2′OH), 2.54 (m, 1H, H6α),2.47 (d, J=4.4 Hz, 1H, 7OH), 2.36 (s, 3H, 4Ac), 2.30 (m, 2H, H14α,H14β), 2.24 (s, 3H, 10Ac), 1.88 (m, 1H, H6α), 1.78 (br s, 3H, Me18),1.74 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H,Me16).

In view of the above, it will be seen that the several objects of theinvention are achieved.

As various changes could be made in the above compositions and processeswithout departing from the scope of the invention, it is intended thatall matter contained in the above description be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A metal alkoxide having the formula:

wherein M is a metal, E₁ and E₂ and the carbon atom to which they areattached define a carbocyclic or heterocyclic skeleton having thebicyclic, tricyclic or tetracyclic taxane nucleus and E₃ is hydrogen orhydrocarbon.
 2. The metal alkoxide of claim 1 wherein E₃ is hydrogen. 3.The metal alkoxide of claim 1 wherein M is a Group IA, IIA, IIIA,lanthanide, actinide, transition, Group IIIA, Group IVA, Group VA orGroup VIA metal.
 4. The metal alkoxide of claim 1 wherein E₁ and E₂ andthe carbon atom to which they are attached define a carbocyclic skeletonhaving the bicyclic taxane nucleus, E₃ is hydrogen and M is a Group IA,IIA, IIIA, lanthanide, actinide, transition, Group IIIA, Group IVA,Group VA or Group VIA metal.